DESCRIPTION (provided by investigator): The goal of this project is to identify variants in environmentally responsive genes that modulate the genetic susceptibility of individuals to amyotrophic lateral sclerosis (ALS). Considerable progress has been made in identifying genes (SOD1 and ALSIN) and loci (chromosomes 9, 15, 16, 18, 2 and x) in the familial form of ALS but the etiology of sporadic ALS (SALS) remains unknown. To address the genetic contribution to SALS we have collected a large set of trios, case-control and discordant sib-pairs resources and now have sufficient material to test specific hypothesis. To fulfill our goal we will initially use a functional candidate approach to screen genetic variants in 410 environmentally responsive genes in two cohorts of ALS patients and controls. The associations detected with ALS will be verified in a second cohort of 500 case-controls subjects. We have used bioinformatics tools to mine a fairly comprehensive list of environmentally responsive genes from several databases including those identified by the NIEHS. We will screen variants (SNP's) in these genes using a high-throughput genotyping system and examine the SALS susceptibility and phenotype for allelic association to these genes. The initial screen will employ 250 trios and 500 case controls subjects. Promising candidates will be validated using a second set of 500 cases and controls and in discordant sibpairs. Furthermore, we will examine the genes associated with SALS for gene-gene and gene-environment interactions. Identification of gene variants associated with SALS or with the SALS sub-phenotypes (e.g. Age-at-onset, site-of-onset, bulbar/spinal etc.) will allow us to test genes in the entire pathway to which the candidate gene belongs. This project will therefore allow a focused study of environmentally responsive genes using a large resource of family and singleton ALS cohorts and will generate resources to investigate new approaches to ALS pathogenesis and in formulating rational treatment. The causes of sporadic ALS are largely unknown, and rational therapy is therefore not possible. A genetic susceptibility to environmental toxicity is considered to underlie ALS. We have a large cohort of ALS patients, siblings, parents and control subjects. We will use this unique resource to analyze the association of DNA variations in genes involved in detoxification of environmental toxins to ALS, and test the identified genes for their interaction with environmental exposures. This study will open fresh ground to investigative mechanisms of disease in ALS for formulation of rational treatment. [unreadable] [unreadable] [unreadable]